Regional Brain Abnormalities Associated

Context: Cannabis is the most widely used illicit drug
in the developed world. Despite this, there is a paucity
of research examining its long-term effect on the human
brain.

Objective: To determine whether long-term heavy cannabis
use is associated with gross anatomical abnormalities
in 2 cannabinoid receptor–rich regions of the brain,
the hippocampus and the amygdala.
Design: Cross-sectional design using high-resolution
(3-T) structural magnetic resonance imaging.
Setting: Participants were recruited from the general
community and underwent imaging at a hospital research
facility.Participants: Fifteen carefully selected long-term (_10
years) and heavy (_5 joints daily) cannabis-using men
(mean age, 39.8 years; mean duration of regular use, 19.7
years) with no history of polydrug abuse or neurologic/
mental disorder and 16 matched nonusing control subjects
(mean age, 36.4 years).Main Outcome Measures: Volumetric measures of
the hippocampus and the amygdala combined with measures
of cannabis use. Subthreshold psychotic symptoms
and verbal learning ability were also measured.
Results: Cannabis users had bilaterally reduced hippocampal
and amygdala volumes (P=.001), with a relatively
(and significantly [P=.02]) greater magnitude of
reduction in the former (12.0% vs 7.1%). Left hemisphere
hippocampal volume was inversely associated with
cumulative exposure to cannabis during the previous 10
years (P=.01) and subthreshold positive psychotic symptoms
(P_.001). Positive symptom scores were also associated
with cumulative exposure to cannabis (P=.048).
Although cannabis users performed significantly worse
than controls on verbal learning (P_.001), this did not
correlate with regional brain volumes in either group.
Conclusions: These results provide new evidence of exposure-
related structural abnormalities in the hippocampus
and amygdala in long-term heavy cannabis users and
corroborate similar findings in the animal literature. These
findings indicate that heavy daily cannabis use across protracted
periods exerts harmful effects on brain tissue and
mental health.
Arch Gen Psychiatry. 2008;65(6):694-701

THERE IS CONFLICTING
evidence regarding the
long-term effects of regular
cannabis use. Although
growing literature suggests
that long-term cannabis use is associated
with a wide range of adverse health
consequences,1-4 many people in the community,
as well as cannabis users themselves,
believe that cannabis is relatively
harmless and should be legally available.
With nearly 15 million Americans using
cannabis in a given month, 3.4 million
using cannabis daily for 12 months or
more, and 2.1 million commencing use every
year,5 there is a clear need to conduct
robust investigations that elucidate the
long-term sequelae of long-term cannabis
use.
The strongest evidence against the notion
that cannabis is harmless comes from
the animal literature6-9 in which longterm
cannabinoid administration has been
shown to induce neurotoxic changes in the
hippocampus, including decreases in neuronal
volume, neuronal and synaptic density,
and dendritic length of CA3 pyramidal
neurons. Although such work suggests
that exposure to cannabinoids may be neurotoxic
in animals, much less is known
about the neurobiologic consequences of
long-term cannabis exposure in humans.
Only a handful of brain imaging studies
have been conducted in human cannabis
users, with inconsistent findings reported.
Early cannabis research using
pneumoencephalography10 reported cerebral
atrophy in a small sample (N=10)
of cannabis users, but further studies using
computed tomography11-13 did not detect
any abnormalities, despite the potential
confounds of polydrug use, comorbid neurologic/
psychiatric diagnoses, and a lack
of appropriate comparison groups.